In American men, cancer of the prostate gland (CaP) continues to be one of the most frequently occurring malignancies accounting for approximately 29% of all new cancer cases. It is estimated that approximately 180,400 new cases of CaP will be diagnosed in the year 2000, and approximately 31,900 CaP-related deaths are predicted. Therefore, it is warranted to identify our efforts towards the development of novel approaches against CaP. Chemoprevention by naturally occurring or synthetic compounds could be a potential strategy for the management of cancer. Sanguinarine, derived from the root of Sanguinaria canadendid, is a benzophenanthridine alkaloid that is believed to posses anti-tumor properties. Recently, we showed that sanguinarine, at micromolar doses, caused apoptosis in human squamous carcinoma (A431) but not in the formal epidermal keratinocytes (NHEK) (Ahmed et al Clinical Cancer Research, In Press). Sanguinarine treatment also resulted in growth inhibition and apoptotic death of human prostate cancer cell viz. LNCaP, DU145 and PC-34. Further, we also found that sanguine treatment inhibited TNFalpha-mediated activation of NF- kappaB a pleiotropic transcription factor that has been shown to be associated with the development of cancer, in A431 and LNCaP cells. The current proposal capitalizes on these novel observations and has three aims. Firstly, employing a androgen-sensitive and insensitive human prostate carcinoma cells LNCaP and DU145 respectively, we will define the role of apoptosis during cell growth inhibition by sanguinarine. Secondly, we will investigate the involvement of NF-kappaB-pathway in sanguinarine-mediated apoptosis in these prostate cancer cells. Finally, employing athymic nude mice implanted with both types of human prostate carcinoma cells, we will investigate the relevance of the outcome of our in vitro studies to the in vivo situation. The central hypothesis of the work proposed is that sanguinarine will impart chemopreventive and possibly chemotherapeutic effects against prostate cancer via a modulation of NFkappa-B- pathway-mediated apoptosis. A corollary to this hypothesis that will be tested in the in vivo studies planned in this proposal is that sanguinarine treatment will reduce serum PSA levels that is regarded as A prognostic marker of prostate cancer burden in humans. Successful completion of this proposal will define i) the potential for sanguinarine against CaP, and ii) the molecular mechanism(s) associated with the biological response of sanguinarine.